# US 11,896,686 B2 · Hyperbranched polyglycerol-coated particles and methods of making and using thereof

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- Number: US 11,896,686 B2
- Document ID: US11896686B2
- Status: Granted
- Kind: B2
- Application number: 17/842,376
- Filed: 2022-06-16
- Published: 2022-10-13
- Granted: 2024-02-13
- Earliest claimed: 2014-05-09
- Assignees: Yale University
- Applicants: Yale University
- Inventors: Yang Deng; Asiri Ediriwickrema; William M. Saltzman
- Web page: https://patentgrep.com/patent/US11896686B2

## CPC

- A61K 8/0241: {Containing particulates characterized by their shape and/or structure (see also A61K8/04, A61K8/11, and A61K8/14, further aspects are classified in A61K2800/40 and subcodes)}
- A61K 8/90: Block copolymers (A61K8/89 takes precedence)
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 35/00: Antineoplastic agents
- A61Q 17/04: Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
- C07C 59/06: Glycolic acid
- C07C 59/08: Lactic acid
- C08G 83/005: {Hyperbranched macromolecules}
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 2800/412: Microsized, i.e. having sizes between 0.1 and 100 microns
- A61K 2800/413: Nanosized, i.e. having sizes below 100 nm
- A61K 2800/624: by macromolecular compounds
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS

## Abstract

Core-shell particles and methods of making and using thereof are described herein. The core is formed of or contains one or more hydrophobic materials or more hydrophobic materials. The shell is formed of or contains hyperbranched polyglycerol (HPG). The HPG coating can be modified to adjust the properties of the particles. Unmodified HPG coatings impart stealth properties to the particles which resist non-specific protein absorption and increase circulation in the blood. The hydroxyl groups on the HPG coating can be chemically modified to form functional groups that react with functional groups and adhere the particles to tissue, cells, or extracellular materials, such as proteins.

## Claims

### Claim 1

Solid particles comprising a plurality of amphiphilic polymers comprising a poly(hydroxy acid) polymer covalently bound to hyperbranched polyglycerol, wherein the particles comprise:
(a) a core comprising the poly(hydroxy acid) polymer;
(b) a shell comprising the hyperbranched polyglycerol, wherein one or more vicinal hydroxyl groups in the hyperbranched polyglycerol are functionalized with aldehydes, and
(c) one or more therapeutic agents comprising topoisomerase inhibitors, tyrosine kinase inhibitors, anti-inflammatories, or a combination thereof.

### Claim 2 (depends on 1)

The particles of claim 1, wherein the targets of the tyrosine kinase inhibitors are cytoplasmic.

### Claim 3 (depends on 1)

The particles of claim 1, wherein the poly(hydroxy acid) is selected from the group consisting of poly(lactic acid), poly(glycolic acid), and poly(lactic-co-glycolic acid).

### Claim 4 (depends on 3)

The particles of claim 3, wherein the poly(hydroxy acid) is poly(lactic acid).

### Claim 5 (depends on 1)

The particles of claim 1, wherein at least one of the one or more therapeutic agents are encapsulated within the particles.

### Claim 6 (depends on 1)

The particles of claim 1, wherein the therapeutic agents are topoisomerase inhibitors.

### Claim 7 (depends on 6)

The particles of claim 6, wherein the topoisomerase inhibitors are camptothecins.

### Claim 8 (depends on 7)

The particles of claim 7, wherein the camptothecins are selected from the group consisting of camptothecin, irinotecan, topotecan, and a combination thereof.

### Claim 9 (depends on 1)

The particles of claim 1, wherein the therapeutic agents are tyrosine kinase inhibitors.

### Claim 10 (depends on 1)

The particles of claim 1, wherein the therapeutic agents are anti-inflammatories.

### Claim 11

Particles comprising a plurality of amphiphilic polymers comprising poly(lactic acid) polymer covalently bound to hyperbranched polyglycerol, wherein the particles comprise:
(a) a core comprising the poly(lactic acid) polymer;
(b) a shell comprising the hyperbranched polyglycerol, wherein one or more vicinal hydroxyl groups in the hyperbranched polyglycerol are functionalized with aldehydes, and
(c) one or more therapeutic agents comprising camptothecins.

### Claim 12

Particles comprising a plurality of amphiphilic polymers comprising poly(lactic acid) polymer covalently bound to hyperbranched polyglycerol, wherein the particles comprise:
(a) a core comprising the poly(lactic acid) polymer;
(b) a shell comprising the hyperbranched polyglycerol, wherein one or more vicinal hydroxyl groups in the hyperbranched polyglycerol are functionalized with aldehydes, and
(c) one or more therapeutic agents comprising tyrosine kinase inhibitors.

### Claim 13 (depends on 1)

A method of making the particles of claim 1, the method comprising:
(i) mixing a solution containing an organic solvent and the plurality of amphiphilic polymers and the one or more therapeutic agents with an aqueous solvent, and
(ii) evaporating the organic solvent to form the particles.

### Claim 14 (depends on 13)

The method of claim 13, wherein contacting the solution with the aqueous solvent in step (i) forms an emulsion.

### Claim 15 (depends on 13)

The method of claim 13, wherein the amphiphilic polymer comprises poly(lactic acid), poly(glycolic acid), or poly(lactic-co-glycolic acid) covalently bonded to the hyperbranched polyglycerol.

### Claim 16 (depends on 15)

The method of claim 15, wherein the amphiphilic polymer comprises poly(lactic acid) covalently bonded to the hyperbranched polyglycerol.

### Claim 17 (depends on 15)

The method of claim 15, wherein the topoisomerase inhibitors are camptothecins.

### Claim 18 (depends on 1)

A method of treating cancer or inflammation in a subject, the method comprising administering to the subject a pharmaceutical composition containing the particles of claim 1.